Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA 90095, USA.
Epidemiology. 2010 Jan;21(1):87-94. doi: 10.1097/EDE.0b013e3181c15ec6.
Human, animal and cell models support a role for pesticides in the etiology of Parkinson disease. Susceptibility to pesticides may be modified by genetic variants of xenobiotic enzymes, such as paraoxonase, that play a role in metabolizing some organophosphates.
We examined associations between Parkinson disease and the organophosphates diazinon, chlorpyrifos, and parathion, and the influence of a functional polymorphism at position 55 in the coding region of the PON1 gene (PON1-55). From 1 January 2001 through 1 January 2008, we recruited 351 incident cases and 363 controls from 3 rural California counties in a population-based case-control study. Participants provided a DNA sample, and residential exposure to organophosphates was determined from pesticide usage reports and a geographic information system (GIS) approach. We assessed the main effects of both genes and pesticides in unconditional logistic regression analyses, and evaluated the effect of carrying a PON1-55 MM variant on estimates of effects for diazinon, chlorpyrifos, and parathion exposures.
Carriers of the variant MM PON1-55 genotype exposed to organophosphates exhibited a greater than 2-fold increase in Parkinson disease risk compared with persons who had the wildtype or heterozygous genotype and no exposure (for diazinon, odds ratio = 2.2 [95% confidence interval = 1.1-4.5]; for chlorpyrifos, 2.6 [1.3-5.4]). The effect estimate for chlorpyrifos, was more pronounced in younger-onset cases and controls (<or=60 years) (5.3 [1.7-16]). No increase in risk was noted for parathion.
The increase in risk we observed among PON1-55 variant carriers for specific organophosphates metabolized by PON1 underscores the importance of considering susceptibility factors when studying environmental exposures in Parkinson disease.
人体、动物和细胞模型均支持农药在帕金森病发病机制中的作用。对农药的易感性可能会因代谢某些有机磷酸酯的外源生物酶（如对氧磷酶）的遗传变异而改变。
我们研究了帕金森病与有机磷农药敌敌畏、毒死蜱和对硫磷之间的关联，以及 PON1 基因编码区第 55 位的功能多态性（PON1-55）的影响。在一项基于人群的病例对照研究中，我们于 2001 年 1 月 1 日至 2008 年 1 月 1 日期间，从加利福尼亚州的 3 个农村县招募了 351 名新发病例和 363 名对照。参与者提供了 DNA 样本，通过农药使用报告和地理信息系统（GIS）方法确定了对有机磷农药的居住暴露情况。我们在非条件逻辑回归分析中评估了基因和农药的主要作用，并评估了携带 PON1-55 MM 变体对敌敌畏、毒死蜱和对硫磷暴露的影响估计值的影响。
与具有野生型或杂合基因型且无暴露的个体相比，携带有机磷农药暴露的变异 MM PON1-55 基因型的个体帕金森病风险增加了两倍以上（敌敌畏的比值比=2.2[95%置信区间=1.1-4.5]；毒死蜱的比值比=2.6[1.3-5.4]）。在发病年龄较轻的病例和对照者（<60 岁）中，氯吡硫磷的效应估计值更为明显（5.3[1.7-16]）。未观察到对硫磷风险增加。
我们观察到 PON1-55 变异携带者对 PON1 代谢的特定有机磷农药的风险增加，这突出表明在研究帕金森病中的环境暴露时，应考虑易感性因素。
